1. Field of the Invention
The present invention relates to peptides that can inhibit the infection of HIV, and more particularly, to peptides consisting of less than 30 amino acids which can introduce a helix capping motif into a peptide derived from C-terminal helical region (its 628-646th amino acid region) of gp41, an envelope glycoprotein of HIV, as well as consisting of the symmetrical bivalent peptide through the introduction of a branched amino acid, Fmoc-Lys(Fmoc)-OH at C-terminus of its peptide, and induce a more stable helical structure thus inhibiting the infection of HIV.
2. Description of the Related Art
Host cell infection by HIV is mediated by the binding between envelope glycoproteins of HIV and receptors of a host cell such as CD4 and chemokine receptors (Berger, AIDS, 11, S3-16, 1997; Doranz et al., Immunol. Res., 16, 15-28, 1997; Moore et al., Current Opin. Immunol., 9, 551-562, 1997). When gp120 of HIV binds CD4 of a host cell, gp120 undergoes a structural change so that it can bind a chemokine receptor in a host cell. Once the binding is completed, a hydrophobic amino terminal fusion peptide region of gp41 of HIV can be inserted in the membrane of a host cell. Then, three gp41 envelope glycoproteins form a six-stranded a-helical bundle, in which three N-peptides associate to form the central trimeric coiled-coil and three C-peptides pack obliquely in an antiparalllel manner on the surface of the coiled-coil core. This bundle structure is involved in a fusion between HIV cell membrane and a host cell membrane as a result thus enabling the core of HIV to penetrate into the cytoplasm of a host cell (Chan and Kim, Cell, 93, 681-684, 1998). Gp41, a glycoprotein present on the envelope of HIV, is also involved in the fusion between HIV envelope and human cell membrane. Gp41 consists of a fusion peptide which exhibits an activity on cell membrane fusion, an N-terminal helical region, a C-terminal helical region, a transmembrane region, and a cytoplasmic region. Peptides derived from N- and C-helical region of the extracellular domain of gp41 can bind to each other in an aqueous solution due to their strong interactions and thus form a very stable complex consisting of six helices from three N-peptides and three C-peptides. The above interaction between the two helical regions is known to play a crucial role in the activity of cell fusion as well as the structural stability of gp41 protein itself. Therefore, it becomes obvious form the above that any substance that can inhibit the above interaction between the two helical regions will be able to inhibit the stability as well as the function of gp41, which will eventually lead to the inhibition of HIV infection thus becoming a promising therapeutic agent for AIDS treatment. In particular, hydrophobic interactions among three nonpolar residues (Trp628, Trp631, and IIe635 of gp41) of C34 peptide (the 628th-661st amino acid) derived from C-terminus of gp41 and a cavity formed by C-terminal portion of the coiled-coil core are known to be important in antiviral activities. These structural features imply that the formation of a helical structure is a prerequisite for the binding between a C-peptide and an N-terminal helical region. DP178, a 36-mer peptide(638th-673rd amino acid, SEQ ID NO.1: YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF) derived from C-terminal helical region of gp41 is also known to inhibit gp41-mediated cell fusion, and 1 ng/mL of DP178 has about 90% inhibitory activity on cell fusion mediated by gp41. DP178 is known to inhibit cell fusion by binding an N-terminal helical region of gp4l thus preventing its interaction with the C-terminal helical region of gp41. DP178 and its modified peptides having an antiviral activity consisted of at least 34-36 amino acids and they did not form a secondary structure in an aqueous solution. However, when the ith and the (i+7)th amino acid residues of a peptide consisting of 27 amino acids derived from C-terminus of gp41 without an antiviral activity are chemically cross-linked, the above peptide formed a helical structure and showed an antiviral activity. Hence, helical stabilization of the C-peptides appears to be an important factor in promoting binding affinity for the coiled-coil motif of gp41 as well as for anti-HIV activity(Judice, Proc. Natl. Acd. Sci. USA, 94,13426-13430, 1997).
However, thus obtained peptides have drawbacks as specified below. First, a peptide should have at least 30 amino acids to be able to inhibit gp41-mediated cell fusion and this incurs a lot of expense in synthesizing those peptides. Second, there requires an additional method to chemically link amino acid residues in order to obtain a peptide with a helical structure or a bivalent sequence. Therefore, it has been a long-felt need to develop a peptide with an antiviral activity which consists of relatively less amino acids compared to traditional peptides which have more than 36 amino acids and forms a stable helical structure in an aqueous solution without necessitating complicated post-synthetic modifications.
To solve the above problems, the inventors of the present invention introduced a helix-capping motif into both N-terminus and C-terminus of a peptide derived from a C-terminal helical region of gp41 or substituted into amino acids that can facilitate the formation of a helical structure in order to stabilize a helical structure of a peptide and subsequently confirmed that the peptides can inhibit the cell fusion of HIV via a strong interaction with N-terminal helical region of gp41. The object of the present invention is to provide peptides that can inhibit the infection of HIV containing helix-capping motifs at both ends of a 19-mer peptide (628th-646th region) derived from C-terminus of gp41, an envelope glycoprotein of HIV.